This program project application continues to be focused on the etiology of gastric cancer with a multidisciplinary approach. It builds on the findings of previous applications which have resulted in the formulation of a general hypothesis of gastric cancer causation. The specific segments of the chain of causation and the specific agents acting upon them will be tested. The first project tests two previously identified etiologic factors: the role of antioxidants (ascorbic acid and beta-carotene) and the role of the Helicobacter pylori. It is done via a randomized blind clinical trial with intermediate end points. The detailed study of the end-points is the subject of the second project: histopathology. The third project continues to explore the role of in vivo nitrosation in gastric causation. The previous finding of a positive correlation between nitrate excretion and N-nitrosoproline formation in patients with intestinal metaplasia will be tested and further explored with 15NO3 feeding. The role of reduced ascorbic acid will be studied by direct measurements in the gastric juice of patients with and without chronic atrophic gastritis. The fourth project addresses the natural history of Helicobacter infection and its effects on cell replication and nuclear abnormalities. The fifth project explores the molecular abnormalities of different stages of the process focusing on specific markers of activation of selected proto-oncogens and inactivation of a suppressor gene putatively involved in the tumorigenesis process. DNA will be extracted from gastric mucosa at different stages of the process to study activating mutations in H-ras, Ki-ras and N-ras genes, p 53 gene and TPR-MET oncogene rearrangements.